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Abstract From October 2014 to February 2019, local authorities in Townsville, North Queensland, Australia continually introduced Wolbachia-infected mosquitoes to control seasonal outbreaks of dengue infection. In this study, we develop a mathematical modelling framework to estimate the effectiveness of this intervention as well as the relative dengue transmission rates of Wolbachia-infected and wild-type mosquitoes. We find that the transmission rate of Wolbachia-infected mosquitoes is reduced approximately by a factor of 20 relative to the uninfected wild-type population. In addition, the Townsville Wolbachia release program led to a 65% reduction in predicted dengue incidence during the release period and over 95% reduction in the 24 months that followed. Finally, to investigate the potential impact of other Wolbachia release programs, we use our estimates of relative transmissibility to calculate the relationship between the reproductive number of dengue and the proportion of Wolbachia-infected mosquitoes in the vector population.

Abstract Wolbachia intracellular bacteria successfully reduce the transmissibility of arthropod-borne viruses (arboviruses) when introduced into virus-carrying vectors such as mosquitoes. Despite the progress made by introducing Wolbachia bacteria into the Aedes aegypti wild-type population to control arboviral infections, reports suggest that heat-induced loss-of-Wolbachia-infection as a result of climate change may reverse these gains. Novel, supplemental Wolbachia strains that are more resilient to increased temperatures may circumvent these concerns, and could potentially act synergistically with existing variants. In this article, we model the ecological dynamics among three distinct mosquito (sub)populations: a wild-type population free of any Wolbachia infection; an invading population infected with a particular Wolbachia strain; and a second invading population infected with a distinct Wolbachia strain from that of the first invader. We explore how the range of possible characteristics of each Wolbachia strain impacts mosquito prevalence. Further, we analyse the differential system governing the mosquito populations and the Wolbachia infection dynamics by computing the full set of basic and invasive reproduction numbers and use these to establish stability of identified equilibria. Our results show that releasing mosquitoes with two different strains of Wolbachia did not increase their prevalence, compared with a single-strain Wolbachia-infected mosquito introduction and only delayed Wolbachia dominance.

A controlled drug delivery system is preferable to traditional drug administration because it can supply the drug continuously and ensure on-demand bioavailability. The production of silica/polymer composite delivery material is expensive due to the use of alkoxysilane silica precursors. As bamboo is an abundant plant in Africa, we investigated the use of bamboo stems as an alternative silica starting material. The ash from the bamboo stem was mixed with polycaprolactone (PCL) solution to produce a (SiO2/PCL) composite, which was then loaded with the drug, tetracycline hydrochloride (TCH), to test in vitro degradability and controlled-release in phosphate-buffered saline (PBS). Scanning electron microscopy, X-ray diffractometry and Fourier transform infrared spectroscopy were used to examine the structure, phase composition, and chemical bond properties of the material. The TCH release profile was determined using an ultraviolet (UV) spectrophotometer. The SiO2/PCL composite showed a high capacity for drug loading. The composite released TCH in a consistent and sustained way, and showed regulated degradability in PBS. As a result, the use of bamboo stem-derived silica in the formulation of SiO2/PCL for continuous TCH delivery shows considerable cost-benefit potential for a safe, regulated drug delivery strategy. Significance: • This study shows the benefit of using bamboo stem as an alternative silica source to alkoxysilanes. • SiO2/PCL composites can be employed for the sustained delivery of drugs while providing congruent degradation. • This study can serve as a benchmark for further utilisation of bamboo stem as a low-cost silica precursor.

Abstract Background Incidence of malaria and anaemia are of public health importance especially in pregnant women in endemic regions, due to the negative health consequences to the mother and fetus. This study aimed to assess the pattern of falciparum malaria infection and anaemia, based on malaria prevention methods practiced by participants. Methods A semi-structured tool was used to capture information on demographic, socio-economic and malaria prevention practices from 113 pregnant women attending antenatal clinics in 2 peri-urban health facilities in Lagos, southwest Nigeria. Malaria microscopy was conducted and haematocrit was measured. Logistic regression analysis was performed on the data collated from the survey. Results The prevalence of anaemia among pregnant women was 87.2%. The mean (± sd) packed cell volume (PCV) (%) of the 22 (19.5%) infected subjects (26.8 ± 6.6), was significantly lower (t = −2.60, P value = 0.007) than that of the 91 (80.5%) uninfected subjects (30.8 ± 6.0). The prevalence of infection was highest in the 3rd trimester (n = 40, 35.4%) at 27.5% (11/40) and among those in their first pregnancy (n = 32, 28.3%) at 25.0% (8/32). There was a significant difference (t = −2.23, P-value = 0.01) in the mean PCV % of pregnant women who consumed herbal teas in pregnancy (28.2 ± 5.2) compared to those who did not (30.8 ± 6.6). Regression analysis showed that first pregnancy, anti-malarial use and insecticide-treated nets use the night before study had increased odds of malaria infection in participants (OR = 1.35, P = 0.006, 95% CI 0.52−2.49; OR = 2.3, P = 0.005, 95% CI 0.14−0.41; OR = 1.92, P = 0.001, 95% CI 0.62−5.98) while intermittent preventive treatment (IPT) participation and formal education were strongly and significantly associated with lower risk of parasitaemia (OR = 0.95, P = 0.025, 95% CI 0.41−2.26; OR = 0.44, P = 0.005, 95% CI 0.34−10.50). Conclusion Interventions that will reduce malaria and moderate to severe anaemia, especially in a first pregnancy, should include education on the correct use of long-lasting insecticide-treated bed nets (LLIN), IPT and the dangers of herbal teas in pregnancy.

Vector control methods are considered effective in averting dengue transmission. However, several factors may modify their impact. Of these controls, chemical methods, in the long run, may increase mosquitoes’ resistance to chemicides, thereby decreasing control efficacy. The biological methods, which may be self-sustaining and very effective, could be hampered by seasonality or heatwaves (resulting in, e.g., loss of Wolbachia infection). The environmental methods that could be more effective than the chemical methods are under-investigated. In this study, a systematic review is conducted to explore the present understanding of the effectiveness of vector control approaches via dengue transmission models.

Morphogenetic traits are observable characters inherited by individuals from their parents in autosomal dominant or recessive manner and expressed differently among populations. The differences in inheritance and expression of these traits usually form the basis of diversity and variation among populations. This study was carried out to ascertain the distribution, inheritance pattern and association of morphogenetic traits among students of the University of Lagos, Nigeria. Ten morphogenetic traits which includes, widow's peak, hitchhiker's thumb, cleft chin, tongue rolling, earlobe attachment, dimpled cheeks, bent little finger, ability to taste phenylthiocarbamide(PTC), mid-phalangeal hair and polydactyly were assessed by observations among 1000 randomly selected undergraduate students of the University. Association studies between traits were carried out using chi-square test of independence with a threshold of 5% level of significance. The study revealed the distributions of the traits as follows: widow's peak present in 36.8%; double jointed hitchhiker's thumb, 46.5%;cleft chin, 19.9%; tongue rollers, 63.9%; free earlobe attachment, 74.6%; dimpled cheeks,22.0%; bent little finger, 36.7%; ability to taste PTC, 42.9%; presence of mid-phalangeal hair,35.35% and polydactyly was found in 6.8% of the participants. Association evaluation showed no significant association between all the morphogenetic traits and gender except for dimpled cheeks (χ2 = 5.26, p = 0.022). Ability to taste PTC was found to be associated with tongue rolling (χ2 = 4.46, p = 0.035); widow's peak was associated with cleft chin (χ2 = 11.63, p< 0.01) and dimpled cheeks (χ2 = 5.67, p< 0.05). Dimpled cheek was significantly associated with cleft chin (χ2 = 31.22, p< 0.01). Also, bent little finger was found to be associated with mid-phalangeal hair (χ2 = 7.13, p< 0.01), polydactyly (χ2 = 5.67, p< 0.05) and hitchhiker's thumb (χ2 = 19.24, p< 0.01). More recessive type of traits evaluated were observed among sampled participants, not typed to ethnicity or group. Results obtained in this study are suitable for medicolegal and anthropological studies.

Abstract Background Entomological indices within a specific area vary with climatic factors such as rainfall, temperature and relative humidity. Contributions of such weather parameter fluctuations to the changes in entomological data obtained within a community under implementation of a promising vector control intervention should be taken into account. This study reports on inter-annual changes in entomological indices within two rural communities, one of which was under insecticide-treated durable wall lining (DL) installation. Methods Community-wide DL installation was followed by monthly meteorological data and pyrethrum spray mosquito collections for 2 years in intervention and a similar neighbouring community (control). Human blood meal and sporozoite ELISA tests were conducted on female mosquitoes collected alongside PCR identification of subsamples. Mosquitoes collected at the intervention site were tested in cone susceptibility assays against subsamples of installed DL materials collected on a 6-monthly basis for 2 years. Deltamethrin susceptibility of Anopheles mosquitoes from the intervention site was determined before and after DL installation. Entomological indices in the first and second years were compared within each site. Results Rainfall in the study area increased significantly (t = -3.45, df = 11, P = 0.005) from first to second year. Correlation between rainfall and Anopheles densities in both sites were significant (r = 0.681, P < 0.001). Mosquitoes collected at the intervention site were susceptible (100%) to deltamethrin at baseline but resistant (92%) in the second year. However, subsamples of installed DL materials remained effective (100% mortality) against Anopheles mosquitoes from the intervention site throughout the 6-monthly cone assay exposures. Monthly pyrethrum spray collections showed significant increase in Anopheles densities from first to second year in the control (6.36 ± 1.61 vs 7.83 ± 2.39; t = -3.47, df = 11, P = 0.005), but not in the intervention (2.83 ± 1.86 vs 4.23 ± 3.31; t = -2.03, df = 11, P = 0.067) community. However, mean annual mosquito man-biting rates increased significantly in both intervention (0.88 ± 0.18 vs 1.06 ± 0.38; F (1, 10) = 9.50, P = 0.012) and control (1.45 ± 0.31 vs 1.61 ± 0.34; F (1, 10) = 10.18, p = 0.010) sites along with increase (≥ 1.6 times) in sporozoite rates within intervention (0–2.13%) and control (2.56–4.04%) communities. Conclusions The slight increase in vector density, induced by significant increase in rainfall, led to increased sporozoite infection and significantly increased man-biting rates within the intervention site. These reveal the need for incorporation of integrated vector management strategies to complement DL installation especially in regions with high rainfall and mosquito density. Promising vector control tools such as DL should be evaluated on a long-term basis to reveal the possible effect of weather parameters on control performance and also allow for holistic recommendations.

Arthropod-borne viruses (Arboviruses) continue to generate significant health and economic burdens for people living in endemic regions. Of these viruses, some of the most important (e.g., dengue, Zika, chikungunya, and yellow fever virus), are transmitted mainly by Aedes mosquitoes. Over the years, viral infection control has targeted vector population reduction and inhibition of arboviral replication and transmission. This control includes the vector control methods which are classified into chemical, environmental, and biological methods. Some of these control methods may be largely experimental (both field and laboratory investigations) or widely practised. Perceptively, one of the biological methods of vector control, in particular, Wolbachia-based control, shows a promising control strategy for eradicating Aedes-borne arboviruses. This can either be through the artificial introduction of Wolbachia, a naturally present bacterium that impedes viral growth in mosquitoes into heterologous Aedes aegypti mosquito vectors (vectors that are not natural hosts of Wolbachia) thereby limiting arboviral transmission or via Aedes albopictus mosquitoes, which naturally harbour Wolbachia infection. These strategies are potentially undermined by the tendency of mosquitoes to lose Wolbachia infection in unfavourable weather conditions (e.g., high temperature) and the inhibitory competitive dynamics among co-circulating Wolbachia strains. The main objective of this review was to critically appraise published articles on vector control strategies and specifically highlight the use of Wolbachia-based control to suppress vector population growth or disrupt viral transmission. We retrieved studies on the control strategies for arboviral transmissions via arthropod vectors and discussed the use of Wolbachia control strategies for eradicating arboviral diseases to identify literature gaps that will be instrumental in developing models to estimate the impact of these control strategies and, in essence, the use of different Wolbachia strains and features.

MicroRNA-122 (miR-122) has been identified as a marker of various liver injuries, including hepatitis- virus-infection-, alcoholic-, and non-alcoholic steatohepatitis (NASH)-induced liver fibrosis. Here, we report that the extracellular miR-122 from hepatic cells can be delivered to hepatic stellate cells (HSCs) to modulate their proliferation and gene expression. Our published Argonaute crosslinking immunoprecipitation (Ago-CLIP) data identified several pro-fibrotic genes, including Ctgf, as miR-122 targets in mice livers. However, treating Ctgf as a therapeutic target failed to rescue the fibrosis developed in the miR-122 knockout livers. Alternatively, we compared the published datasets of human cirrhotic livers and miR-122 KO livers, which revealed upregulation of BCL2, suggesting its potential role in regulating fibrosis. Notably, ectopic miR-122 expression inhibited BCL2 expression in human HSC (LX-2) cells). Publicly available ChIP-seq data in human hepatocellular cancer (HepG2) cells and mice livers suggested miR-122 could regulate BCL2 expression indirectly through c-MYC, which was confirmed by siRNA-mediated depletion of c-MYC in Hepatocellular Carcinoma (HCC) cell lines. Importantly, Venetoclax, a potent BCL2 inhibitor approved for the treatment of leukemia, showed promising anti-fibrotic effects in miR-122 knockout mice. Collectively, our data demonstrate that miR-122 suppresses liver fibrosis and implicates anti-fibrotic potential of Venetoclax.

Abstract Background PermaNet® 3.0 is an insecticide synergist-combination long-lasting insecticidal net designed to have increased efficacy against malaria vectors with metabolic resistance, even when combined with kdr. The current study reports on the impact of this improved tool on entomological indices in an area with pyrethroid-resistant malaria vectors in Nigeria. Methods Baseline entomological indices across eight villages in Remo North LGA of Ogun State provided the basis for selection of three villages (Ilara, Irolu and Ijesa) for comparing the efficacy of PermaNet® 3.0 (PN3.0), PermaNet® 2.0 (PN2.0) and untreated polyester nets as a control (UTC). In each case, nets were distributed to cover all sleeping spaces and were evaluated for insecticidal activity on a 3-monthly basis. Collection of mosquitoes was conducted monthly via window traps and indoor resting catches. The arithmetic means of mosquito catches per house, entomological inoculation rates before and during the intervention were compared as well as three other outcome parameters: the mean mosquito blood feeding rate, mean mortality and mean parity rates. Results Anopheles gambiae s.l. was the main malaria vector in the three villages, accounting for >98% of the Anopheles population and found in appreciable numbers for 6–7 months. Deltamethrin, permethrin and lambdacyhalothrin resistance were confirmed at Ilara, Irolu and Ijesa. The kdr mutation was the sole resistance mechanism at Ilara, whereas kdr plus P450-based metabolic mechanisms were detected at Irolu and Ijesa. Bioassays repeated on domestically used PN 2.0 and PN 3.0 showed persistent optimal (100%) bio-efficacy for both net types after the 3rd, 6th, 9th and 12th month following net distribution. The use of PN 3.0 significantly reduced mosquito densities with a ‘mass killing’ effect inside houses. Households with PN 3.0 also showed reduced blood feeding as well as lower mosquito parity and sporozoite rates compared to the PN 2.0 and the UTC villages. A significant reduction in the entomological inoculation rate was detected in both the PN 2.0 village (75%) and PN 3.0 village (97%) post LLIN-distribution and not in the UTC village. Conclusion The study confirms the efficacy of PN 3.0 in reducing malaria transmission compared to pyrethroid-only LLINs in the presence of malaria vectors with P450-based metabolic- resistance mechanisms.

BACKGROUND:The pro-fibrogenic cytokine connective tissue growth factor (CTGF) plays an important role in the development and progression of fibrosis in many organ systems, including liver. However, its role in the pathogenesis of hepatitis C virus (HCV)-induced liver fibrosis remains unclear. METHODS:In the present study, we assessed CTGF expression in HCV-infected hepatocytes using replicon cells containing full-length HCV genotype 1 and the infectious HCV clone JFH1 (HCV genotype 2) by real-time PCR, Western blot analysis and confocal microscopy. We evaluated transforming growth factor β1 (TGF-β1) as a key upstream mediator of CTGF production using neutralizing antibodies and shRNAs. We also determined the signaling molecules involved in CTGF production using various immunological techniques. RESULTS:We demonstrated an enhanced expression of CTGF in two independent models of HCV infection. We also demonstrated that HCV induced CTGF expression in a TGF-β1-dependent manner. Further dissection of the molecular mechanisms revealed that CTGF production was mediated through sequential activation of MAPkinase and Smad-dependent pathways. Finally, to determine whether CTGF regulates fibrosis, we showed that shRNA-mediated knock-down of CTGF resulted in reduced expression of fibrotic markers in HCV replicon cells. CONCLUSION:Our studies demonstrate a central role for CTGF expression in HCV-induced liver fibrosis and highlight the potential value of developing CTGF-based anti-fibrotic therapies to counter HCV-induced liver damage.

A hallmark of cancer cells is hypermethylation of CpG islands (CGIs), which probably arises from upregulation of one or more DNA methyltransferases. The purpose of this study was to identify the targets of DNMT3B, an essential DNA methyltransferase in mammals, in colon cancer.Chromatin immunoprecipitation with DNMT3B specific antibody followed by CGI microarray identified genes with or without CGIs, repeat elements and genomic contigs in RKO cells. ChIP-Chop analysis showed that the majority of the target genes including P16, DCC, DISC1, SLIT1, CAVEOLIN1, GNA11, TBX5, TBX18, HOXB13 and some histone variants, that harbor CGI in their promoters, were methylated in multiple colon cancer cell lines but not in normal colon epithelial cells. Further, these genes were reactivated in RKO cells after treatment with 5-aza-2'-deoxycytidine, a DNA hypomethylating agent. COBRA showed that the CGIs encompassing the promoter and/or coding region of DCC, TBX5, TBX18, SLIT1 were methylated in primary colorectal tumors but not in matching normal colon tissues whereas GNA11 was methylated in both. MassARRAY analysis demonstrated that the CGI located approximately 4.5 kb upstream of HOXB13 +1 site was tumor-specifically hypermethylated in primary colorectal cancers and cancer cell lines. HOXB13 upstream CGI was partially hypomethylated in DNMT1(-/-) HCT cells but was almost methylation free in cells lacking both DNMT1 and DNMT3B. Analysis of tumor suppressor properties of two aberrantly methylated transcription factors, HOXB13 and TBX18, revealed that both inhibited growth and clonogenic survival of colon cancer cells in vitro, but only HOXB13 abolished tumor growth in nude mice.This is the first report that identifies several important tumor suppressors and transcription factors as direct DNMT3B targets in colon cancer and as potential biomarkers for this cancer. Further, this study shows that methylation at an upstream CGI of HOXB13 is unique to colon cancer.

We investigated the amplitude of medium scale traveling ionospheric disturbances (MSTIDs, with periods 25–100 min) and their dependence on the solar activity using 16 years data of the rapid run‐ionosonde operating at high latitudes (67° $67{}^{\circ}$N, Sodankylä, Finland). A deep learning neural network was applied to ionograms to extract critical frequency of the F2 region (foF2) with a 1 min time resolution. Then, we analyzed the relative amplitude of MSTIDs (i.e., 2δ $2\delta $foF2/foF2), which corresponds to the amplitude of atmospheric gravity waves (AGWs) causing MSTIDs. The amplitude of AGWs propagating upward increases with height due to the decreasing density of the air, and hmF2 varies depending on local time, seasonal and solar activity conditions. To account for this effect, we calculated a corrected MSTID amplitude by normalizing the relative amplitude for the air density at the hmF2. The corrected amplitudes show no clear dependence on F10.7 during winter (0–12 UT), equinox (20‐01 UT) and summer (19‐01 UT), while a positive dependence of corrected amplitudes on F10.7 was observed during winter and equinox, in 14–22 UT and 15–19 UT, respectively. Corresponding to the dependence behaviors of corrected and relative amplitudes, two likely mechanisms of MSTIDs, AGWs from the lower atmosphere and auroral sources, are inferred. Their subsequent roles in the solar activity dependence of MSTID amplitudes were separately discussed, although in reality, the observed dependence is complex and often involves several mechanisms together. Plain Language Summary: HF radio frequencies used for ground and/or space‐ground communications and navigation systems often face challenges due to traveling ionospheric disturbances (TIDs), which can degrade the propagation of radio signals. Employing deep learning for rapid‐run ionosonde data enabled us to monitor TIDs at Sodankylä Geophysical Observatory (SGO) effectively. Daytime TID occurrences are often associated with disturbances triggered from the lower atmosphere (AGWs). However, the increase in hmF2, which reduces the likelihood of AGWs initiated from the lower atmosphere reaching the region of peak ionization, and the expansion of the auroral oval due to frequent substorms, shift the nighttime triggers to auroral electrodynamics in high latitude regions. In this paper, we examine the dependence of MSTID amplitudes on solar activity after applying a new correction approach. Key Points: foF2 obtained from 1 min ionograms through deep learning enabled us to conduct long‐term MSTID investigations in high latitudesCorrection of MSTID amplitudes to the neutral density level at different hmF2 altitudes properly describes the solar activity dependenceCorresponding to the causing mechanisms, the high‐latitude corrected MSTID amplitudes infer different types of dependence on solar activity [ABSTRACT FROM AUTHOR]

The potential of deep learning for the investigation of medium scale traveling ionospheric disturbances (MSTIDs) has been exploited through the Sodankyla rapid-run ionosonde in this statistical study. The complementing observations of the Sodankyla ionosonde with those of the Sodankyla meteor radar reveals the diurnal and seasonal occurrence rate of high-latitude MSTIDs in the recent low solar activity period, 2018-2020. In our results, the daytime, nighttime and dusk MSTIDs are predominantly identified during winter, summer, and equinoctial months, respectively. The winter daytime higher (lower) occurrence rate is well correlated with the lower (higher) altitude of the height of the F2-layer peak (hmF2), and the low occurrence rate of the summer daytime is well correlated with the mesosphere-lower-thermosphere wind shear and higher gradient of temperature. Relatively high occurrence rate (>0.4) of summer nighttime MSTIDs has a general--but not one-to-one agreement--with post-noon to evening IU (eastward auroral current index) inferred ionospheric conductivity. Rather, we see a one-to-one relationship between the summer nighttime MSTIDs and zonal wind shear suggesting that the wind shear-induced electrodynamic processes could play significant roles for higher occurrence rate of MSTIDs. Furthermore, significant MSTIDs with ~0.4 occurrence rate are so far revealed during spring and autumn transition periods. The enhanced nighttime MSTID amplitudes during the equinox are observed to be well correlated with IL index (westward auroral current indicator) suggesting that the particle precipitation during substorms could be the primary cause. [ABSTRACT FROM AUTHOR]